Genetic Variant NM_133444.3:c.479A>C (chr19-42224882-A-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM2PP5_ModerateBP4

The NM_133444.3(ZNF526):c.479A>C(p.Lys160Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ZNF526
NM_133444.3 missense

Scores

Clinical Significance

Likely pathogenic criteria provided, single submitter P:3

Conservation

PhyloP100: 2.20

Variant links:

Genes affected

ZNF526 (HGNC:29415): (zinc finger protein 526) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be active in nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ZNF526 links:

ENSG00000288671 (HGNC:):

ENSG00000288671 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 19-42224882-A-C is Pathogenic according to our data. Variant chr19-42224882-A-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 183288.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-42224882-A-C is described in Lovd as [Pathogenic]. Variant chr19-42224882-A-C is described in Lovd as [Likely_pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.38166898). . Strength limited to SUPPORTING due to the PP5.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ZNF526	NM_133444.3 link	c.479A>C	p.Lys160Thr	missense_variant	Exon 3 of 3	ENST00000301215.8	NP_597701.1	Q8TF50H9ZYJ3
ZNF526	NM_001314033.3 link	c.479A>C	p.Lys160Thr	missense_variant	Exon 3 of 3		NP_001300962.1	Q8TF50H9ZYJ3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ZNF526	ENST00000301215.8 link	c.479A>C	p.Lys160Thr	missense_variant	Exon 3 of 3	1	NM_133444.3	ENSP00000301215.2	Q8TF50
ENSG00000288671	ENST00000678490.1 link	c.91+7175T>G		intron_variant	Intron 1 of 1			ENSP00000502878.1	A0A7I2V2F5
ZNF526	ENST00000710326.1 link	c.479A>C	p.Lys160Thr	missense_variant	Exon 3 of 3			ENSP00000518206.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461848

Hom.:

Cov.:

AF XY:

0.00000275

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Dentici-Novelli neurodevelopmental syndrome

Pathogenic:1

Jan 13, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided

Pathogenic:1

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Pulmonic stenosis;C3714756:Intellectual disability;CN228297:Noonan-like facies

Pathogenic:1

Dec 01, 2014

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Likely pathogenic

Review Status: flagged submission

Collection Method: research

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.45

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.52

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.040

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.69

FATHMM_MKL

Benign

0.45

LIST_S2

Benign

0.67

M_CAP

Benign

0.021

MetaRNN

Benign

0.38

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.43

Sift

Uncertain

0.022

Sift4G

Uncertain

0.030

Polyphen

0.021

Vest4

0.75

MutPred

0.44

Loss of ubiquitination at K160 (P = 0.0116);

MVP

0.25

MPC

0.71

ClinPred

0.42

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over